Process for the preparation of 3,4-dihydroxybutanoic acid and derivatives thereof from substituted pentose sugars

ABSTRACT

A process for the preparation of 3,4-dihydroxybutanoic acid (I) and 3-hydroxy-γ-butyrolactone (V) thereof from a 3-leaving group substituted pentose source is described. In particular, the process relates to the synthesis of (R)-3,4-dihydroxybutanoic acid and (R)-3-hydroxy-γ-butyrolactone from a 3-leaving group substituted L-pentose sugars. The process uses a base and a peroxide to convert the pentose source to the chiral 3,4-dihydroxybutanoic acid compound. The chiral 3,4-dihydroxybutanoic acid can be further converted to 3-hydroxy-γ-butyrolactone by acidification. The chiral compound is useful as a chemical intermediate to the synthesis of various drugs and other products.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

None.

CROSS-REFERENCE TO RELATED APPLICATIONS

None.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to a process for the preparation of3,4-dihydroxybutanoic acid and 3-hydroxy-γ-butyrolactone therefromstarting with a pentose sugar source substituted in the 3-position,preferably in the chiral form. In particular, the process relates to thesynthesis of (R)-3,4-dihydroxybutanoic acid and (R)3-hydroxy-γ-butyrolactone from a substituted L-pentose source. Theprocess uses a base and a peroxide to convert the pentose source tochiral 3,4-dihydroxybutanoic acid. The chiral 3,4-dihydroxybutanoic acidcan be further converted to 3-hydroxy-γ-butyrolactone by acidification.The products are useful to the synthesis of various drugs and naturalproducts.

(2) Description of Related Art

The current art on the oxidation of carbohydrates to3,4-dihydroxybutanoic acid and derivatives describe the transformationof substituted hexoses which are usually only of the D-configurationwhich upon conversion yield only the 3,4-dihydroxybutanoic acid andderivatives in the (S)-configuration. In these reactions, chiral3,4-dihydroxybutanoic acid and derivatives thereof are synthesized fromcarbohydrates by oxidation of 4-substituted hexoses with hydrogenperoxide. The chiral carbon atom is derived from the 5-position of thehexose sugar. Because most naturally occurring hexose sugars are of theD-configuration, this method is good only for preparation of(S)-3,4-dihydroxybutanoic acid and derivatives. In contrast to theposition with hexose sugars, some pentose sugars such as xylose andarabinose occur in considerable amounts in the L-configuration.

There are methods for transforming 3,4-dihydroxybutanoic acid andderivatives to important molecules such as carnitine, however theprocess is extremely problematic starting from the (S)-derivativesbecause the stereochemistry at the 3-position has to be inverted. Theprior art describes chemical and enzymatic processes for the preparationof the (S)-3,4-dihydroxybutanoic acid and derivatives by oxidation ofsugars, but not for the preparation of (R)-3,4-dihydroxybutanoic acidand derivatives.

U.S. Pat. Nos. 4,994,597 and 5,087,751 to K. Inoue et al disclosemethods for making optically active 3,4-dihydroxybutyric acidderivatives by reacting R-3-chloro-1,2-propanediol made by stereoselective microorganism decomposition of racemic3-chloro-1,2-propanediol.

U.S. Pat. No. 5,319,110 to R. Hollingsworth discloses a process forsynthesis of an internal cyclic ester such as a lactone by converting ahexose source, which contains hexose as a substituent and another sugarattached to the hexose substituent in the 4 position via(S)-3,4-dihydroxybutanoic acid as an intermediate. U.S. Pat. No.5,374,773 to R. Hollingsworth discloses a process for the synthesis(S)-3,4-hydroxybutanoic salt by converting a hexose source whichcontains hexose as a substituent and another sugar attached to thehexose substituent in the 4 position via (S)-3,4-dihydroxybutyric acidas an intermediate. U.S. Pat. No. 5,292,939 to R. Hollingsworthdiscloses synthesis of (S)-3,4-dihydroxybutyric acid from substitutedD-hexose.

(S)-3,4-dihydroxybutyric acid and derivatives, such as (S)-1,2,4butanetriol that is formed by its reduction, are important 4-carboncompounds that are pivotal intermediates in the synthesis of variousdrugs and other natural products. These include the preparation ofcompounds such as eicosanoids (E. J. Corey et al. 1978. J. Amer. Chem.Soc. 100: 1942-1943), modified nucleic acid bases (H. Hayashi et al.1973. J. Amer. Chem. Soc. 95: 8749-8757), the polyol function ofmacrolide antibiotics (Y. Mori et al. 1988. Tetrahedron Letts. 29:5419-5422), and (−) aplysistatin, an anticancer agent (H. M. Shieh andG. D. Prestwich. 1982. Tetrahedraon Letts. 23: 4643-4646).

A common route to the (S)-3-hydroxy-γ-butyric acid or butyrolactoneequivalent used in the above synthesis involves the use of malic acid asthe chiral raw material. This is reduced to a triol and the two vicinalhydroxyl groups protected by acetylization with acetone and an acidcatalyst. The remaining primary hydroxyl group is then oxidized to analdehyde or acid and the acetal group is then removed. Preparation of(R) and (S) isomers of gamma-lactone from (R) or (S) malic acid has alsobeen described by Uchikawa et al. 1988. Bull. Chem. Soc. Jpn. 61:2025-2029. These routes have been of academic interest because malicacid is reasonably expensive and two groups have to be reduced to thelevel of an alcohol and one then selectively oxidized.(S)-3-hydroxy-γ-butyrolactone as a synthetic intermediate in the drugindustry is a very expensive material.

Therefore, it is desirable to develop a process for transforming pentosesugars such as xylose and arabinose into useful building blocks for thepreparation of chiral compounds for use in the drug, agri-chemical andadvanced material science industries. In particular, it is desired thata method for oxidizing pentoses which would remove a 1 carbon from thereducing end and an oxygen from the 2-position give either the (R) or(S) isomer of 3,4-dihydroxybutanoic acid and derivatives, usingessentially the same reaction and depending on whether the D or Lpentose is used.

SUMMARY OF THE INVENTION

The present invention provides a process for oxidizing a precursorcompound which is a pentose, a furanose or a pentanal by removing acarbon from the reducing end and an oxygen from the 2-position whichproduces either the (R) or (S) isomer of 3,4-dihydroxybutanoic acid andderivatives. The process uses essentially the same reaction conditionsto produce either the (R) or (S) isomer of 3,4-dihydroxybutanoic acidand derivatives depending on whether a D or L pentose is used as thestarting material. In particular, the invention provides a method forpreparing 3,4-dihydroxybutanoic acid from a pentose, furanose, orpentanal in a reaction mixture comprising a peroxide in the presence ofa base. Further, the invention provides 3-hydroxy-γ-butyrolactone bytreating 3,4-dihydroxybutanoic acid with an acid in the presence ofheat.

Objects

It is therefore an object of the present invention to provide a processfor preparing a chiral 3,4-dihydroxybutanoic acid preferably in a chiralform from a pentose, furanose, or pentanal source. It is further anobject of the present invention to provide a process which is simple,economical and inexpensive. These and other objects will becomeincreasingly apparent by reference to the following description and thedrawings.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the conversion of a pentose sugar substituted at the3-position (R1) to chiral 3,4-dihydroxybutanoic acid (I). Compound (II)is a substituted pentanal, compound (III) is a substituted pyranose, andcompound (IV) is a substituted furanose.

FIG. 2 shows the conversion of chiral 3,4-dihydroxybutanoic acid (I) to3-hydroxy-γ-butyrolactone (V) (gamma-lactone).

FIG. 3 shows the structure for 3,4-O-isopropylidene-L-arabinose.

FIG. 4 shows the structure for 3-O-methyl-L-arabinose.

FIG. 5 shows the structure of 3-O-β-D-galactopyranoysl-D-arabinose.

FIG. 6 shows the structure for 3,4-O-methyl-L-arabinose.

FIG. 7 shows the structure of 3,4-O-isopropylidene-D-arabinose.

FIGS. 8A to 8C show structures of various alkylidene or arylidenesubstituted pentoses. FIG. 8A shows the structure of a3,4-O-isopropylidene pentose. FIG. 8B shows the structure for a2,3-O-isopropylidene pentose. FIG. 8C shows the structure for a3,5-O-benzylidene furanose.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention relates to a process for thepreparation of 3,4-dihydroxybutanoic acid (I) which comprises: reactinga mixture of a 3-leaving group substituted precursor compound selectedfrom the group consisting of a pentose, a furanose and a pentanal of theformulas, for the pentose

for the furanose

for the pentanal

wherein R₁ is a protecting leaving group and wherein R is optionally Hor a protecting leaving group with a solvent containing a peroxide inthe presence of a base to produce (I) and a protonated leaving group;and separating (I) from the mixture. R in the 1, 2, 4, or 5 positionscan be any combination of groups which includes but is not limited tothe group consisting of hydroxy, alkyloxy, aryloxy, acyloxy, halo,sulfonyloxy, sulfate, phosphate. When R is not a hydroxy group, the R isdefined herein as a protecting group and the position it occupies isprotected. The 3-leaving group (R₁) can be any group which includes butis not limited to alkyloxy, aryloxy, acyloxy, halo, sulfonyloxy,sulfate, phosphate.

The present invention particularly relates to a process for theconversion of a pentose source containing a pentose substituted at the3-position to chiral 3,4-dihydroxybutanoic acid and derivatives. Theprocess consists of the oxidation of either an L or D pentose sugar,which causes the removal of the 1-carbon, giving either the (R) or (S)isomer of 3,4-dihydroxybutanoic acid under essentially the same reactionconditions. Thus, oxidation of the L pentose will give rise to the (R)isomer and oxidation of the D pentose will give rise to the (S) isomer.

In particular, the present invention relates to a process for thepreparation of 3,4-dihydroxybutanoic acid (I) which comprises: reactinga mixture of a 3-leaving group substituted-n-pentanal selected from thegroup consisting of 2,4,5-trihydroxy-3-leaving groupsubstituted-n-pentanal, 2,4-dihydroxy-3-leaving group 4-O-protectedsubstituted-n-pentanal, 2-hydroxy-3-leaving group 4,5-di-O-protectedsubstituted-n-pentanal, 4-hydroxy-3-leaving group 2,5-di-O-protectedsubstituted-n-pentanal, 5-hydroxy-3-leaving group 2,4-di-O-protectedsubstituted-n-pentanal, and 3-leaving group 2,4,5-tri-O-protectedsubstituted-n-pentanal with a solvent containing a peroxide in thepresence of a base to produce (I) and a protonated leaving group, andthen separating (I) from the mixture.

In this process, (I) can be produced by providing a 3-leaving groupsubstituted pentose selected from the group consisting of2,4,5-trihydroxy-3-R₁-O-pentose, 2,4-protected-3-R₁-O-pentose,4-protected-3-R₁-O-pentose, 2-protected-3-R₁-O-pentose, and5-protected-3-R₁-O-pentose in the mixture wherein R₁ is the leavinggroup and protected is the protecting group R. In particular embodimentsof the invention, the 3-leaving group pentose can be a 3-leaving groupsubstituted furanose (IV) or a 3-leaving group substituted pyranose(III).

Thus, in one particular embodiment of the invention, the 3-leaving groupsubstituted furanose (IV) is selected from the group consisting of2,5-dihydroxy-3-leaving group substituted furanose,5-protected-2-hydroxy-3-leaving group substituted furanose,2-protected-5-hydroxy-3-leaving group substituted furanose, and a2,5-protected-3-leaving group substituted furanose in the mixture.

In another particular embodiment of the invention, the substitutedpyranose (III) is selected from the group consisting of2,4-dihydroxy-3-leaving group substituted pyranose,2-O-protected-4-hydroxy-3-leaving group substituted pyranose,4-O-protected-2-hydroxy-3-leaving group substituted pyranose, and a2,4-O-protected-3-leaving group substituted pyranose in the mixture. Ina preferred embodiment of the invention (I), (III), (IV) and (V) areeach a single chiral compound.

The present invention further relates to a process for the preparationof 3-hydroxy-γ-butyrolactone (V) which comprises: reacting a mixture ofa 3-leaving group substituted precursor compound selected from the groupconsisting of a pentose, a furanose and a pentanal of the formulas,

for the pentose

for the furanose

for the pentanal

wherein R₁ is a protecting leaving group and wherein R is optionally Hor a protecting leaving group with a solvent containing a peroxide inthe presence of a base to produce (I) and a protonated leaving group;and treating the (I) with an acid and heat to form the3-hydroxy-γ-butyrolactone (V).

In particular, the present invention relates to a process for thepreparation of 3-hydroxy-γ-butyrolactone (V) which comprises: reacting amixture of a 3-leaving group substituted precursor compound selectedfrom the group consisting of 2,4,5-trihydroxy-3-leaving groupsubstituted-n-pentanal, 2,4-dihydroxy-3-leaving group 4-O-protectedsubstituted-n-pentanal, 2-hydroxy-3-leaving group 4,5-di-O-protectedsubstituted-n-pentanal, 4-hydroxy-3-leaving group 2,5-di-O-protectedsubstituted-n-pentanal, 5-hydroxy-3-leaving group 2,4-di-O-protectedsubstituted-n-pentanal, and 3-leaving group 2,4,5-tri-O-protectedsubstituted-n-pentanal with a solvent containing a peroxide in thepresence of a base to produce (I) and a protonated leaving group, thentreating the (I) with an acid and heat to form the3-hydroxy-γ-butyrolactone(V).

In this process, (V) can be produced by providing a 3-leaving groupsubstituted pentose selected from the group consisting of2,4,5-trihydroxy-3-R₁-O-pentose, 2,4-protected-3-R-O-pentose,4-protected-3-R₁-O-pentose, 2-protected-3-R₁-O-pentose, and5-protected-3-R₁-O-pentose in the mixture wherein R₁ is the leavinggroup and protected is the protecting group R. In particular embodimentsof the invention, the 3-leaving group pentose can be a 3-leaving groupsubstituted furanose (IV) or a 3-leaving group substituted pyranose(III).

Thus, in one particular embodiment of the invention, the 3-leaving groupsubstituted furanose (IV) is selected from the group consisting of2,5-dihydroxy-3-leaving group substituted furanose,5-protected-2-hydroxy-3-leaving group substituted furanose,2-protected-5-hydroxy-3-leaving group substituted furanose, and a2,5-protected-3-leaving group substituted furanose in the mixture.

In another particular embodiment of the invention, the substitutedpyranose (III) is selected from the group consisting of2,4-dihydroxy-3-leaving group substituted pyranose,2-O-protected-4-hydroxy-3-leaving group substituted pyranose,4-O-protected-2-hydroxy-3-leaving group substituted pyranose, and a2,4-O-protected-3-leaving group substituted pyranose in the mixture. Ina preferred embodiment of the invention (I), (III), (IV) and (V) areeach a single chiral compound. In a preferred embodiment of theinvention (I), (III), (IV) and (V) are each a single chiral compound.

The present invention further relates to a process for the preparationof unsaturated lactone (VI) which comprises: reacting a mixture of a2,4,5-O-R 3-leaving group substituted compound selected from the groupconsisting of a pentose, a furanose and a pentanal with a solventcontaining peroxide and a base to produce 3,4-dihydroxybutanoic acid (I)and a protonated leaving group; treating the (I) with an acid and heatto form the 3-hydroxy-γ-butyrolactone (V); and distilling under reducedpressure in the presence of the acid to produce the unsaturated lactone(VI).

In particular, the present invention relates to a process for thepreparation of unsaturated lactone (VI) which comprises: reacting amixture of a 3-leaving group substituted-n-pentanal selected from thegroup consisting of 2,4,5-trihydroxy-3-leaving groupsubstituted-n-pentanal, 2,4-dihydroxy-3-leaving group 4-O-protectedsubstituted-n-pentanal, 2-hydroxy-3-leaving group 4,5-di-O-protectedsubstituted-n-pentanal, 4-hydroxy-3-leaving group 2,5-di-O-protectedsubstituted-n-pentanal, 5-hydroxy-3-leaving group 2,4-di-O-protectedsubstituted-n-pentanal, and 3-leaving group 2,4,5-tri-O-protectedsubstituted-n-pentanal with a solvent containing a peroxide in thepresence of a base to produce (I) and a protonated leaving group,treating the (I) with an acid and heat to form the3-hydroxy-γ-butyrolactone (V); and then distilling under reducedpressure in the presence of the acid to produce the unsaturated lactone(VI). In this process, (VI) can be produced by providing a 3-leavinggroup substituted pentose such as 3-leaving group substituted furanose(IV) or 3-leaving group substituted pyranose (III), selected from thegroup consisting of 2,4,5-trihydroxy-3-R-O-pentose,2,4-protected-3-R-O-pentose, 4-protected-3-R-O-pentose,2-protected-3-R-O-pentose, and 5-protected-3-R-O-pentose in the mixturewhere R is the leaving group. In one embodiment of the process, the3-leaving group substituted furanose (IV) is selected from the groupconsisting of 2,5-dihydroxy-3-leaving group substituted furanose,5-protected-2-hydroxy-3-leaving group substituted furanose,2-protected-5-hydroxy-3-leaving group substituted furanose, and a2,5-protected-3-leaving group substituted furanose in the mixture. Inanother embodiment of the process, the substituted pyranose (III) isselected from the group consisting of 2,4,5-trihydroxy-3-leaving groupsubstituted pyranose, 2,5-O-protected-3,4-dihydroxy-3-leaving groupsubstituted pyranose, 4,5-O-protected-2,3-dihydroxy-3-leaving groupsubstituted pyranose, and a 2,4-O-protected-3,5-dihydroxy-3-leavinggroup substituted pyranose in the mixture.

In the preferred process of the present invention, the pentose isselected from the group consisting of D and L isomers. Examples ofpentoses that can be used are arabinose, ribulose, xylose and lyxose. Inparticular, the pentose can be a 3-leaving group substituted pentosewith a saccharide as the leaving group. In a preferred embodiment, thepentose is selected from the wherein the pentose is selected from thegroup consisting of 3-O-methyl pentose, 3-O-alkyl-pentose,3,4-O-alkylidene-pentose, 3,5-O-alkylidene-pentose,2,3-O-alkylidene-pentose, 3,4-O-arylidene-pentose,3,5-O-arylidene-pentose, 2,3-O-arylidene-pentose, 3-O-acyl-pentose,3,4-O-acylidene-pentose, 2,3-O-acylidene-pentose,3,5-O-acylidene-pentose, ester-substituted-pentoses and 3-O-sugarsubstituted-pentose wherein the sugar provides the leaving group. In aparticular embodiment the pentose is selected from the group consistingof 3,4-O-isopropylidene-pentose, 2,3-O-isopropylidene-pentose, and3,5-O-benzylidene-pentose. FIGS. 8A and 8B are examples of3,4-O-isopropylidene and 2,3-O-isopropylidene substituted pentoses, andFIG. 8C is an example of 3,5-O-benzylidene substituted pentose.

Furthermore, in the process of the present invention the 3-leaving groupis selected from the group consisting of alkyloxy, aryloxy, acyloxy,halo, sulfonyloxy, sulfate, phosphate, and a saccharide and wherein (I),(III) and (IV) are each a single chiral compound. In a preferredembodiment, (I) is an (R) isomer or an (S) isomer and the pentose isselected from the group consisting of 3-O-methyl-arabinose,3,4-O-methyl-arabinose, 3,4-O-isopropylidene-arabinose,3-O-galactopyranosyl-arabinose, and 2,3-O-isopropylidene-arabinose. In amost preferred embodiment the 2,4,5-trihydroxy-3-substituted-n-pentanalor other substituted pyranose or furanose is a D-sugar or a L-sugar.

In performing the process of the present invention, the peroxide isselected from the group consisting of hydrogen peroxide, alkaline earthperoxides, and combinations thereof, and the base is selected from thegroup consisting of alkaline earths, alkaline metals, substitutedammonium hydroxides and combinations thereof. The selection of theperoxide and the base is well within the skill of the art. In performingthe process, the solvent is selected from the group consisting of waterand water miscible organic solvents, methanol, isopropanol, dioxane,tetrahydrofuran (THF), dimethylformamide and combinations thereof. In apreferred embodiment of the process, the peroxide is hydrogen peroxideand the base is sodium hydroxide.

Preferably the sodium hydroxide or potassium hydroxide molarconcentration is between 1 to 2 fold of the total 3-leaving groupsubstituted pentose. The 3-leaving group substituted pentose source ispreferably at least 0.05 percent up to 80% by weight per volume of thereaction mixture. Preferably the reaction of the base with the 3-leavinggroup substituted pentose source is conducted for at least 4 hours andpreferably between about 10 and 24 hours. The reaction is conducted at apreferred temperature between 25° C. and 80° C. The base is betweenabout 0.005 M and 0.2 M, wherein the hydrogen peroxide is between about0.05 M and 0.2 M and wherein the 3-leaving group substituted pentose isat least about 0.05 percent by weight per volume of the reactionmixture.

Therefore, according to the present invention, pentose sugars can beconverted to chiral 3,4-dihydroxybutanoic acid by oxidation with aperoxide source and a base if the pentose sugar is substituted with aleaving group at the 3-position. FIG. 1 shows the conversion of a3-leaving group substituted pyranose or furanose to3,4-dihydroxybutanoic acid. The reaction proceeds by oxidation with aperoxide source and a base. As long as the 3-position is substitutedwith a leaving group, the substituted sugar is converted to3,4-dihydroxybutanoic acid. In FIG. 1, R in the 1, 2, 4, or 5 positionsis can be any combination of groups which includes but is not limited tothe group consisting of hydroxy, alkyloxy, aryloxy, acyloxy, halo,sulfonyloxy, sulfate, phosphate. When R is not a hydroxy group it isdefined as a protecting group and the position it occupies is protected.The 3-leaving group R₁ can be any group which includes but is notlimited to alkyloxy, aryloxy, acyloxy, halo, sulfonyloxy, sulfate,phosphate.

While the nature of the 3-leaving group is quite variable, the mosteasily obtained functionality is an alkoxy group. Hence 3-O-methylpentoses are good substrates as are certain acetals such as3,4-O-isopropylidene, 2,3-O-isopropylidene and 3,5-O-benzylidene pentoseacetals (FIGS. 8A, 8B and 8C, respectively). Acyl and other estersubstitutions and disaccharides such as3-O-β-D-galactopyranosyl-D-arabinose are also useful substrates. Thus,in addition to pentoses having 3-leaving groups, pentoses having3,4-leaving groups, 2,3-leaving groups and 3,5-leaving groups are allencompassed by the present invention.

The dihydroxybutyric acid can be converted to the corresponding3-hydroxy-γ-butyrolactone (gamma-lactone) by acidification with amineral acid, concentrating and then extracting the product into anorganic solvent such as ethyl acetate, chloroform, dimethylformamide, ortetrahydrofuran (THF) as shown in FIG. 2. Gamma-lactone can bedehydrated, on heating in the presence of acid and under reducedpressure to yield the unsaturated lactone (2(5H)-furanone). Treatment ofthe gamma-lactone with hydrogen bromide in acetic acid in the presenceof ethanol will readily yield (R)-4-bromo-3-hydroxybutanoic acid ethylester, a key fragment in chiral 3-hydroxy fatty acid synthesis.

The preferred reactions are shown in schemes I, II and III as follows:

Scission of the bond between the two carbonyl groups of D (FIG. 1)resulting from the degradation of the 3-leaving group substitutedpentose source occurs in the presence of alkaline hydrogen peroxidebefore any competing reactions to yield 3,4-dihydroxybutanoic acid (I)which is stable to further reaction. On acidification of the reactionmixture, (I) undergoes spontaneous cyclization to yield gamma-lactone,3-hydroxy-γ-butyrolactone (V). The gamma-lactone can be converted to theunsaturated lactone (VI) by distillation of the acidic reaction mixtureunder reduced pressure.

3,4-dihydroxybutanoic acid (I), HCOOH, R₁OH and ROH were the onlyproducts formed from the 3-leaving group substituted pentose such asarabinose when treated with alkaline hydrogen peroxide at 65° C. for 10hours. Acidification of the reaction mixture and concentration todryness led to complete conversion of the 3,4-hydroxybutanoic acid tothe gamma lactone. This could be isolated by chromatography on silicagel or converted to the unsaturated lactone by distillation of theacidic mixture under reduced pressure.

It is to be understood that the chirality of any of the3,4-hydroxybutanoic acid (I), gamma-lactone (V) and unsaturated lactone(VI) products is dependant on the chirality of the 3-leaving groupsubstituted pentose. For example a 3-leaving group substituted L-pentosewill yield only (R) 3,4-hydroxybutanoic acid (I), gamma-lactone (V), orunsubstituted lactone (VI), whereas a 3-leaving group substitutedD-pentose will yield only (S) 3,4-hydroxybutanoic acid (I),gamma-lactone (V), or unsubstituted lactone, 2(5H)-furanone (VI).

The process of the present invention opens the way to the preparation,in high yield, of large quantities of valuable chiral building blocksfrom a cheap, renewable, natural resource. These chiral building blockscan be used in the pharmaceutical, chemical, and polymer industries andreduce dependence on petrochemicals.

The following examples are intended to promote a further understandingof the present invention.

EXAMPLE 1

This example was performed to demonstrate the conversion of3,4-O-isopropylidene-L-arabinose (FIG. 3) to (R)-3,4-dihydroxybutanoicacid and then (R)-3-hydroxy-γ-butyrolactone (gamma-lactone) usinghydrogen peroxide and sodium hydroxide according to the process of thepresent invention.

3,4-O-isopropylidene-L-arabinose (30 grams) was treated with 2700 ml of0.36% sodium hydroxide and 27 grams of 30% hydrogen peroxide. Themixture was heated at 65° C. for 10 hours to form the3,4-dihydroxybutanoic acid. Afterwards, the 3,4-dihydroxybutanoic acidwas extracted with one volume of ethyl acetate and concentrated to asyrup.

To form the gamma-lactone, the 3,4-dihydroxybutanoic acid formed aboveand concentrated to a syrup was acidified to pH 1 with 6 M sulfuricacid, and the acidified syrup concentrated at 40° C. until no moresolvent was removed. Then the syrup was extracted with 1.5 liters ofethyl acetate. The ethyl acetate layer was concentrated to yield 15.5grams (96%) of (R)-3-hydroxy-γ-butyrolactone. The product was greaterthan 90% pure as judged by gas chromatography. Chiral GC analysis on acyclodextrin phase showed that there was greater than 99.8% of the(R)-3-hydroxy-γ-butyrolactone product.

EXAMPLE 2

This example was performed to demonstrate the conversion of3,4-O-isopropylidene-L-arabinose to (R)-3,4-dihydroxybutanoic acid andthen (R)-3-hydroxy-γ-butyrolactone (gamma-lactone) using hydrogenperoxide and sodium hydroxide according to a modification of the processof the present invention.

The oxidation was carried out on 60 grams of3,4-O-isopropylidene-D-arabinose as in Example 1 except that the volumesof the liquids were considerably reduced but the desired concentrationof the hydrogen peroxide and sodium hydroxide were maintained by pumpingin the solutions. Therefore, the acetal which was dissolved in 800 ml ofwater and the sodium hydroxide (40 grams) which was dissolved in 300 mlof water and the hydrogen peroxide (60 grams) which was dissolved in 300ml of water were added to the solution heated at 56° C. over a 6 hourperiod. After addition of the solutions was completed, the heating wascontinued for a further three hours. Then the 3,4-dihydroxybutanoic acidwas isolated as described in Example 1. The yield and purity wassimilar.

The (R)-3-hydroxy-γ-butyrolactone product was prepared from the3,4-dihydroxybutanoic acid as described in Example 1. The yield andpurity was similar.

EXAMPLE 3

This example was performed to demonstrate the conversion of3,4-O-methyl-L-arabinose (FIG. 6) to (R)-3,4-dihydroxybutanoic acid andthen (R)-3-hydroxy-γ-butyrolactone (gamma-lactone) using hydrogenperoxide and sodium hydroxide according to the process of the presentinvention.

3,4-O-methyl-L-arabinose (30 grams) was treated with 2700 ml of 0.36%sodium hydroxide and 27 grams of 30% hydrogen peroxide. The mixture washeated at 65° ^(C.) for 10 hours. Afterwards, the 3,4-dihydroxybutanoicacid was extracted with one volume of ethyl acetate and concentrated toa syrup.

To form the gamma-lactone, the 3,4-dihydroxybutanoic acid formed aboveand concentrated to a syrup was acidified to pH 1 with 6 M sulfuricacid, and the acidified syrup concentrated at 40° C. until no moresolvent was removed. Then the syrup was extracted with 1.5 liters ofethyl acetate. The ethyl acetate layer was concentrated to yield 95%(R)-3-hydroxy-γ-butyrolactone. The product was greater than 95% pure asjudged by gas. chromatography. The optical purity was greater than99.8%.

EXAMPLE 4

This example was performed to demonstrate the conversion of3-O-β-D-galactopyranosyl-D-arabinose (FIG. 5) to(S)-3,4-dihydroxybutanoic acid and then (S)-3-hydroxy-γ-butyrolactone(gamma-lactone) using hydrogen peroxide and sodium hydroxide accordingto the process of the present invention.

3-O-β-D-galactopyranosyl-D-arabinose (30 grams) was treated with 2700 mlof 0.36% sodium hydroxide and 27 grams of 30% hydrogen peroxide. Themixture was heated at 65° C. for 10 hours. Afterwards, the3,4-dihydroxybutanoic acid was extracted with one volume of ethylacetate and concentrated to a syrup.

To form the gamma-lactone, the 3,4-dihydroxybutanoic acid formed aboveand concentrated to a syrup was acidified to pH 1 with 6 M sulfuricacid, and the acidified syrup concentrated at 40° C. until no moresolvent was removed. Then the syrup was extracted with 1.5 liters ofethyl acetate. The ethyl acetate layer was concentrated to yield 85%(R)-3-hydroxy-γ-butyrolactone. The product was greater than 90% pure asjudged by gas chromatography. The optical purity was greater than 99.8%.

EXAMPLE 5

This example was performed to demonstrate the conversion of3,4-O-isopropylidene-D-arabinose (FIG. 7) to (S)-3,4-dihydroxybutanoicacid and then to (S)-3-hydroxy-γ-butyrolactone (gamma-lactone) usinghydrogen peroxide and sodium hydroxide according to the process of thepresent invention.

2,3-O-isopropylidene-D-arabinose (30 grams) was treated with 2700 ml of0.36% sodium hydroxide and 27 grams of 30% hydrogen peroxide. Themixture was heated at 65° C. for 10 hours. Afterwards, the3,4-dihydroxybutanoic acid was extracted with one volume of ethylacetate and concentrated to a syrup.

To form the gamma-lactone, the 3,4-dihydroxybutanoic acid formed aboveand concentrated to a syrup was acidified to pH 1 with 6 M sulfuricacid, and the acidified syrup concentrated at 40° C. until no moresolvent was removed. Then the syrup was extracted with 1.5 liters ofethyl acetate. The ethyl acetate layer was concentrated to yield 60%(S)-3-hydroxy-γ-butyrolactone. The product was greater than 85% pure asjudged by gas chromatography. The optical purity was greater than 99.8%.

EXAMPLE 6

Unsaturated lactone (2(5H)-furanone) is prepared from3-hydroxy-γ-butyrolactone (gamma-lactone). After acidification andconcentration of the gamma-lactone synthesized according to any one ofExamples 1, 2, 3, 4, or 5, it is subjected to distillation under reducedpressure to yield a liquid that boils at 60° C. (25 mm Hg) whichcontains glycolic acid and water. A later fraction is collected at abath temperature of 160° C. which is redistilled to give 2(5H)-furanone.Optionally, the product can be redistilled to remove any residualgamma-lactone.

While the present invention is described herein with reference toillustrated embodiments, it should be understood that the invention isnot limited hereto. Those having ordinary skill in the art and access tothe teachings herein will recognize additional modifications andembodiments within the scope thereof. Therefore, the present inventionis limited only by the Claims attached herein.

We claim:
 1. A process for the preparation of 3,4-dihydroxybutanoic acid(I) which comprises: (a) reacting a mixture of a 3-leaving groupsubstituted precursor compound selected from the group consisting of apentose, a furanose and a pentanal of the formulas, for the pentose

for the furanose

for the pentanal

wherein R₁ is a protecting leaving group and wherein R is optionally Hor a protecting leaving group with a solvent containing a peroxide inthe presence of a base to produce (I); and (b) separating the (I) fromthe mixture.
 2. The process of claim 1 wherein the 3,4-dihydroxybutanoicacid is produced by providing a substituted pentose as the compoundselected from the group consisting of 2,4,5-trihydroxy-3-leaving groupsubstituted-n-pentanal, 2,4-dihydroxy-3-leaving group 4-O-protectedsubstituted-n-pentanal, 2-hydroxy-3-leaving group 4,5-di-O-protectedsubstituted-n-pentanal, 4-hydroxy-3-leaving group 2,5-di-O-protectedsubstituted-n-pentanal, 5-hydroxy-3-leaving group 2,4-di-O-protectedsubstituted-n-pentanal, and 3-leaving group 2,4,5-tri-O-protectedsubstituted-n-pentanal.
 3. The process of claim 2 wherein the pentose isselected from the group consisting of 3-O-methyl pentose,3-O-alkyl-pentose, 3,4-O-alkylidene-pentose, 3,5-O-alkylidene-pentose,2,3-O-alkylidene-pentose, 3,4-O-arylidene-pentose,3,5-O-arylidene-pentose, 2,3-O-arylidene-pentose, 3-O-acyl-pentose,3,4-O-acylidene-pentose, 2,3-O-acylidene-pentose,3,5-O-acylidene-pentose, ester-substituted-pentoses and 3-O-sugarsubstituted-pentose wherein the sugar provides the leaving group.
 4. Theprocess of claim 2 wherein the substituted pentose is selected from thegroup consisting of 3,4-O-isopropylidene-pentose,2,3-O-isopropylidene-pentose, and 3,5-O-benzylidene-pentose.
 5. Theprocess of claim 2 wherein the 3-leaving group substituted pentose isselected from the group consisting of D and L isomers.
 6. The process ofclaim 2 wherein the 3-leaving group substituted pentose is selected fromthe group consisting of 3-O-methyl-arabinose, 3,4-O-esthyl-arabinose,3,4-O-isopropylidene-arabinose, 3-O-galactopyranosyl-arabinose, and2,3-O-isopropylidene-arabinose.
 7. The process of claim 1 wherein the3-leaving group substituted compound is a 3-leaving group substitutedfuranose.
 8. The process of claim 7 wherein the 3-leaving groupsubstituted furanose is selected from the group consisting of2,5-dihydroxy-3-leaving group substituted furanose,5-O-protected-2-hydroxy-3-leaving group substituted furanose,2-O-protected-5-hydroxy-3-leaving group substituted furanose, and a2,5-O-protected-3-leaving group substituted furanose.
 9. The process ofclaim 1 wherein the 3-leaving group substituted compound is a 3-leavinggroup substituted pyranose.
 10. The process of claim 9 wherein the3-leaving group substituted pyranose is selected from the groupconsisting of 2,4-dihydroxy-3-leaving group substituted pyranose,2-O-protected-4-hydroxy-3-leaving group substituted pyranose,4-O-protected-2-hydroxy-3-leaving group substituted pyranose, and2,4-O-protected-3-leaving group substituted pyranose in the mixture. 11.The process of any one of claim 1, 2, 7, or 9 wherein the3,4-dihydroxybutanoic acid is a single chiral compound.
 12. The processof any one of claims 1, 2, 7, or 9 wherein the peroxide is selected fromthe group consisting of hydrogen peroxide, alkaline earth peroxides, andcombinations thereof and wherein the base is selected from the groupconsisting of alkaline earths, alkaline metals, substituted ammoniumhydroxides and combinations thereof.
 13. The process of any one ofclaims 1, 2, 7, or 9 wherein the peroxide is hydrogen peroxide and thebase is sodium hydroxide.
 14. The process of any one of claims 1, 2, 7,or 9 wherein the solvent is selected from the group consisting of water,methanol, isopropanol, dioxane, tetrahydrofuran (THF), dimethylformamideand combinations thereof.
 15. The process of any one of claims 1, 2, 7,or 9 wherein the leaving group is selected from the group consisting ofalkyloxy, aryloxy, acyloxy, halo, sulfonyloxy, sulfate, phosphate, andsaccharide.
 16. The process of any one of claims 1, 2, 7, or 9 whereinthe leaving group is selected from the group consisting of acyl,alkyloxy, aryloxy, acyloxy, halo, sulfonyloxy, sulfate, phosphate, and asaccharide, and wherein the 3,4-dihydroxybutanoic acid is a singlechiral compound.
 17. The process of any one of claims 1, 2, 7, or 9wherein the 3,4-dihydroxybutanoic acid is an R isomer or an S isomer.18. The process of any one of claims 1, 2, 7, or 9 wherein the 3-leavinggroup substituted-n-pentanal is a D-sugar or a L-sugar.